Precision coordination of therapeutic and prophylactic antibiotics to reduce infection, toxicity, and emergence of resistance following acute abdominal surgery

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Acute appendicitis is the most common abdominal surgical emergency in the world, with a lifetime risk of 8.6% in males and 6.9% in females. In the U.S., acute appendicitis affects > 280,000 individuals and contributes to 1 million patient days of admission each year. Surgical site infection (SSI) rates following appendectomy for uncomplicated, non-perforated appendicitis remain unacceptably high. A recent review reported pelvic abscess rates of 9.4% following appendectomy. The highest risks for microbial contamination of the peritoneum occur when the appendix is transected. Regardless of surgical technique, the retained appendiceal stump ALWAYS exposes appendiceal mucosa and luminal bacteria to the normally sterile peritoneal cavity. It is thus critical that optimal antibiotic tissue exposure occurs during this operative risk window. Antibiotic intervention for acute appendicitis is complex. Therapeutic antibiotics are initiated empirically in the emergency department, often hours before the appendectomy (usually a 4-18 hour wait). Thus, at the time of surgery, there are already therapeutic antibiotics on board, and the role of prophylactic antibiotics is unclear. To date, there has been no consensus on the blended use of therapeutic and prophylactic antibiotics for acute surgeries, and in many cases, prophylaxis is not administered because therapeutic antibiotics have already been administered. Unfortunately, in these instances antibiotic tissue levels are likely below the minimum inhibitory concentration at the time of appendiceal transection due to the short half-life and lack of protocoled dose timing relative to surgical incision. Consequently, the appendix, a known microbiome reservoir for the colon, has its lumen open to the peritoneum during appendectomy, guaranteeing some level of tissue and peritoneal microbial contamination during the surgery, increasing risk for SSI and abscess formation. A more personalized method of dosing antibiotics in patients with acute appendicitis could reduce SSI risk, limit unnecessary antibiotic use, reduce overdosing risks, and curb the development of antibiotic resistance. We hypothesize that personalized antibiotic dosing based on time to surgical appendectomy can optimize tissue antibiotic exposure at the surgical site, avoid use of unnecessary antibiotics (selective antibiotic resistance pressure), and reduce toxicity. Our Specific Aims are therefore to 1) characterize the plasma, tissue and surgical site tissue concentration of therapeutic antibiotics in patients undergoing appendectomy; 2) design a precision dosing nomogram for therapeutic beta-lactam antibiotics using quantitative tissue PK-PD modeling and simulation that factors antimicrobial susceptibility distributions, patient demographics and morphotypes as well as timing to achieve optimal tissue exposure at appendectomy; and 3) pilot and evaluate the effectiveness of a precision blended antibiotic treatment and prophylaxis nomogram for appendectomy in preparation for future large-scale dissemination by surgical quality collaboratives.